Dr. Bailey-Wilson is collaborating with Drs. Barbara and Ronald Klein on analyses of existing family data from the Beaver Dam Eye Study. A private census of the town and township of Beaver Dam, Wisconsin was performed and all individuals between the ages of 43-84 were asked to enroll, given extensive eye examinations and asked to fill out a questionnaire that measures environmental risk factor exposures. Of the 5925 eligible people, 4926 (83.1%) participated. Within this dataset, there are 1,247 people from 564 sibships with at least 2 members in each sibship having complete age, sex and examination results. We have analyzed STRP genome-wide scan (GWS) data on the entire Beaver Dam cohort of families for glaucoma, IOP, refractive error, myopia, hyperopia, and various forms of cataracts. A SNP genome-wide scan to increase information content is underway. We are currently selecting SNPs for the finemapping of Chromosome 19 for IOP, and 2 smaller glaucoma known regions on chromosomes 5 and 6, regions that showed evidence of linkage in our GWS. Two papers presenting our linkage results for myopia/hyperopia/refractive error and for IOP/glaucoma were published this fiscal year.[unreadable] [unreadable] A study of the genetics of myopia with Dr. Dwight Stambolian is ongoing. Dr. Stambolian has collected pedigrees with myopia from 5 populations. Analyses of refractive error in the Ashkenazi Jewish and Amish families have revealed evidence of a QTL on chromosome 1; one paper has been published this year and another is in preparation. New families have been genotyped for a genome wide scan and have been analyzed. A paper presenting these linkage results for myopia in new Ashkenazi families has been submitted and a paper describing our myopia linkage results in a set of African-American families and a set of Caucasian familes is in preparation. In addition, a dense map of SNP markers has been genotyped in the Ashkenazi families to follow up our previous chromosome 22 linkage, and significant association has been found. Several genes were sequenced in our linked families and in normal individuals, and one potentially functional polymorphism was found to be significantly associated with increased risk of myopia. Additional studies are underway. A set of about 1500 SNPs are being genotyped in our Ashkenazi and Amish families to follow up the linkage of refractive error on chromosome 1.[unreadable] [unreadable] Dr. Bailey-Wilson is a member of a collaborative study of Attention Deficit Hyperactivity Disorder, collaborating with Drs. Max Muenke and Dr. Mauricio Arcos-Burgos of NHGRI and University of Antioquia, Columbia. Dr. Bailey-Wilson's role is to help with study design and to serve as advising statistical geneticist on the project. Genome-wide scan genotyping and linkage analysis has been completed on the first set of families followed by finemapping. We have previously shown evidence of linkage of ADHD to 4q132, 5q333, 11q22, and 17p11 and evidence for other comorbid psychiatric disorders in these families. A paper is now in press showing evidence for pleiotropic effects of the same genes on both ADHD and comorbid disruptive behavior disorders. Association studies have been performed to followup our linkage results and papers are in preparation.[unreadable] [unreadable] Dr. Bailey-Wilson is collaborating with Drs. Steven Brant and Theodore Bayliss of Johns Hopkins University School of Medicine, with the International IBD Consortium and with the Middle Atlantic African American Inflammatory Bowel Disease Study. Dr. Bailey-Wilson also is collaborating with Dr. Brant and Dr. Carolien Panhuysen of Boston University on analyses of IBD data. Linkage and association studies of genome-wide scan and fine mapping data are ongoing. A paper presenting some of these results was published this year. Finally, Drs. Bailey-Wilson and Doan, have worked with Dr. Brant to type markers in additional candidate regions and to analyze these data for linkage and association analysis, and to reanalyze Dr. Brant?s data including environmental covariate data. A paper presenting these results is in preparation.[unreadable] [unreadable] Dr. Bailey-Wilson is collaborating with Dr. Hasan Albacha-Hejazi of the Syrian Arab Republic, Dr. Diego Wyszynski of Boston University and Dr. Terri Beaty of Johns Hopkins School of Public Health on a linkage study of oral clefts. Data collection is ongoing in the Syrian Arab Republic. New Syrian families have been genotyped for genome-wide scan markers and analyses of these data are ongoing.[unreadable] [unreadable] Dr. Bailey-Wilson is working with Drs. Forbes Porter of NIH and Elaine Tierney of Kennedy Krieger on a genetic study of autism. Evidence for linkage of autistic individuals with hypocholesterolemia has been found and a paper is in preparation. Confirmation in additional data is underway.[unreadable] [unreadable] Another set of projects led by Dr. Priya Duggal, a senior postdoctoral trainee in the Section, encompass the human genetic predisposition to infectious diseases including Visceral leishmaniasis, Amebiasis and HIV/AIDS.[unreadable] [unreadable] Visceral leishmaniasis (VL) is a potentially fatal disease caused by the protozoan Leishmania chagasi that is carried by the sandfly. Our collaorators collected complete clinical and environmental factor data for 1106 members of 216 families living in endemic neighborhoods in Brazil. We conducted a genome wide linkage analysis for VL and the related immune response DTH and identified one interesting region for VL on chromosome 9, and 3 interesting regions for DTH on chromosomes 15, 19 and 13 in these linkage studies. A manuscript is in preparation. In our case-control studies of mucosal and cutaneous leishmaniasis we identified a functional SNP in IL-6 that is associated with individuals developing mucosal versus cutaneous leishmaniasis. Additional SNPs in IL-6 were genotyped and we have also now collected extended pedigrees from the cases to determine if there is a family based association. A paper was published this fiscal year.[unreadable] [unreadable] Amebiasis is a large contributor to diarrheal disease in the developing world, and is caused by infection of the intestine by the parasite Entamoeba histolytica. Infection with E. histolytica is heterogeneous and it is very likely that genetic predispositions/susceptibility influence acquisition and progression of this parasite in humans. Dr. Duggal and her collaborators have recently shown that the IgA immune response to the carbohyrdrate region domain of E. histolytica provides protection from subsequent infections with E. histolytica, although it is not long lived. This finding may be critical to the development of a vaccine for amebiasis. A paper was published this year and another is under review. A dense set of SNPs are currently being genotyped in 90 candidate genes in 450 children from this study and will be analyzed in the next year.[unreadable] [unreadable] Dr. Duggal also aims to understand genetic host susceptibility to HIV/AIDS, using a cohort of 3000 injection drug users in Baltimore, Maryland that participate in the AIDS Link to Intravenous Experience (ALIVE). Population based genetic studies including this cohort have identified numerous candidate genes that affect HIV/AIDS disease progression. Part of the APOBEC compex is the CUL5 factor; we have identified a cluster of haplotypes driven by 3 SNPs that influences progression to AIDS, and also has a strong influence on CD4 cell counts. There is also a strong additive interaction with our previous finding in APOBEC3G. A paper is under review.